Breaking barriers: NEK2 inhibition shines in multiple myeloma treatment
Authors: Christopher Lischer, Heiko Bruns
Journal: Cell Reports Medicine (2023)

In their article, Cheng et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar reveal that NEK2 loss reshapes the tumor microenvironment, reducing tumor-associated macrophages and decreasing T cell exhaustion. They show that this ultimately favors the immune system's anti-cancer response in multiple myeloma. In their article, Cheng et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar reveal that NEK2 loss reshapes the tumor microenvironment, reducing tumor-associated macrophages and decreasing T cell exhaustion. They show that this ultimately favors the immune system's anti-cancer response in multiple myeloma. Multiple myeloma (MM) is a hematologic malignancy that affects plasma cells in the bone marrow. It is associated with progressive immune dysregulation characterized by effector cell function impairment, loss of myeloma-reactive effector T cell populations, and a bone marrow microenvironment that promotes immune escape. Making up a significant proportion of immune cells in the bone marrow of patients with MM, tumor-associated macrophages (TAMs) play a pivotal role in promoting MM growth, mediating drug resistance, and inhibiting T cells, making them of particular interest for scientific study and therapeutic targeting.2Kawano Y. Moschetta M. Manier S. Glavey S. Görgün G.T. Roccaro A.M. Anderson K.C. Ghobrial I.M. Targeting the bone marrow microenvironment in multiple myeloma.Immunol. Rev. 2015; 263: 160-172https://doi.org/10.1111/imr.12233Crossref PubMed Scopus (261) Google Scholar Despite the recent introduction of novel therapeutic agents including immunomodulatory imide drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies, MM remains a condition with no established curative approach.3Moreau P. How I treat myeloma with new agents.Blood. 2017; 130: 1507-1513https://doi.org/10.1182/blood-2017-05-743203Crossref PubMed Scopus (59) Google Scholar Almost all patients experience a relapse and progression of the disease, with the treatment of relapsed refractory MM remaining a major clinical challenge. Therefore, it has been proposed that an effective therapeutic strategy could involve making the microenvironment inhospitable or overtly hostile to myeloma cells. Given the success of PD-L1- and PD-1-blocking antibodies in Hodgkin's lymphoma4Ansell S.M. PD-1 Blockade in Classic Hodgkin Lymphoma.JCO Oncol. Pract. 2021; 17: 72-73Crossref PubMed Scopus (5) Google Scholar and their high expression on MM cells and T cells, respectively, clinical expectations for the treatment of MM were high. However, clinical trial outcomes have been disappointing thus far as no significant effects have been seen with monotherapy.5Lesokhin A.M. Ansell S.M. Armand P. Scott E.C. Halwani A. Gutierrez M. Millenson M.M. Cohen A.D. Schuster S.J. Lebovic D. et al.Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study.J. Clin. Oncol. 2016; 34: 2698-2704Crossref PubMed Scopus (772) Google Scholar This result is likely attributed to the complex nature of immune dysfunction in the tumor microenvironment in MM, as previously described and discussed in detail in Kawano et al.2Kawano Y. Moschetta M. Manier S. Glavey S. Görgün G.T. Roccaro A.M. Anderson K.C. Ghobrial I.M. Targeting the bone marrow microenvironment in multiple myeloma.Immunol. Rev. 2015; 263: 160-172https://doi.org/10.1111/imr.12233Crossref PubMed Scopus (261) Google Scholar Consequently, the identification of key molecules responsible for mediating the TAM T cell interplay may hold the potential to unlock novel therapeutic approaches to treat MM. NEK2 (never in mitosis A-related kinase 2) is a protein kinase that plays a critical role in regulating the cell cycle and structural maintenance of the centrosome, and its dysregulation has dire consequences for the cell. High expression of NEK2 is associated with induction of chromosomal instability and promotion of cell proliferation.6Fry A.M. The Nek2 protein kinase: a novel regulator of centrosome structure.Oncogene. 2002; 21: 6184-6194Crossref PubMed Scopus (176) Google Scholar Because both functions are hallmarks of cancer, NEK2 has been considered a potential target for cancer therapies. With this in mind, Fenghuang Zhan's research team has already focused on elucidating the importance of NEK2 in B cell development. In prior publications, they demonstrated that overexpression of NEK2 leads to drug resistance and poor outcomes in MM.7Zhou W. Yang Y. Xia J. Wang H. Salama M.E. Xiong W. Xu H. Shetty S. Chen T. Zeng Z. et al.NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.Cancer Cell. 2013; 23: 48-62Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Extending on their work, in this issue of Cell Reports Medicine, Cheng et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar demonstrate in a comprehensive study that environmental blocking of NEK2 delays MM tumor progression by enhancing anti-tumor immunity. Initially, Cheng et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar investigated the effect of NEK2 deletion in two different lymphoma models (Eμ-myc transgenic mice as an aggressive B cell lymphoma model and 5TGM1 as an immunocompetent MM model). In both disease models, loss of NEK2 resulted in reduced tumor burden and significantly prolonged survival. In the MM model, decreased bone lesions could also be observed. Interestingly, transcriptome analysis (RNA sequencing and single-cell RNA sequencing) showed that NEK2-deficient mice exhibited increased expression of immune-related genes, including chemokines (e.g., Cxcl9 and Ccl5), chemokine receptors (e.g., Ccr2 and Cxcr1), interleukins (e.g., Il1b and Il15), and interleukin receptors (e.g., Il2rb and Il12rb2), suggesting that a lack of NEK2 is associated with immune activation. Moreover, low NEK2 expression correlated with an interferon γ (IFN-γ) gene signature (upregulation of CXCL9 and PD-L1) and improved T cell activation. This pattern was also observed at the cellular level (by flow cytometry) in T cells and TAMs, with both effector cell types exhibiting abundant NEK2 expression in the tested lymphoma models. Further, T cells in the NEK2-deficient mice were less skewed toward an exhausted effector memory phenotype, while the number of TAMs was significantly reduced. Moreover, the TAMs displayed a reduced immunosuppressive phenotype. This observation aligns with data gathered in myeloid progenitor cells in which NEK2 was found to be essential for the generation of functional immunosuppressive TAMs. In a reanalysis of public data (University of Arkansas for Medical Sciences archive and CoMMpass dataset), Chen et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar showed that high NEK2 expression in patients with MM was accompanied by both shorter overall survival and progression-free survival. Likewise, analysis of bone marrow biopsies by mass cytometry (CyTOF) showed that patients with MM with high NEK2 expression in MM cells also had impaired T cell function. Particularly, it was observed that the IFN-γ/PD-L1 signaling pathway was suppressed. Thus, inhibition of NEK2 with the specific inhibitor INH154 resulted in upregulation of PD-L1 on both MM cells and TAMs. Consequently, Chen et al.1Cheng Y. Sun F. Alapat D.V. Wanchai V. Mery D. Guo W. Cao H. Zhu Y. Ashby C. Bauer M.A. et al.High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.Cell Rep. Med. 2023; 4: 101214https://doi.org/10.1016/j.xcrm.2023.101214Abstract Full Text Full Text PDF Google Scholar tested INH154 in combination with a PD-L1 antibody in a pre-clinical MM model (Vκ∗MYC MM mouse model) to potentially increase its efficacy. In fact, this innovative combinatorial approach resulted in a significantly reduced tumor load and significantly extended survival. These results provide compelling evidence that targeting NEK2 may help overcome immune evasion in MM, which encourages further clinical investigation. Modulation of selected components of the tumor microenvironment to maximize efficacy and minimize toxicity may be an essential feature of novel therapeutic approaches aimed at eradicating residual MM cells and finding a cure. In particular, combination therapies of therapeutic antibodies and IMiDs show improved efficacy in clinical trials in MM compared with monotherapy.8Richardson P.G. Jagannath S. Moreau P. Jakubowiak A.J. Raab M.S. Facon T. Vij R. White D. Reece D.E. Benboubker L. et al.Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study.Lancet. Haematol. 2015; 2: e516-e527Abstract Full Text Full Text PDF PubMed Google Scholar However, studies combining IMiDs with checkpoint blockades have not been successful.9Mateos M.V. Blacklock H. Schjesvold F. Oriol A. Simpson D. George A. Goldschmidt H. Larocca A. Chanan-Khan A. Sherbenou D. et al.Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial.Lancet. Haematol. 2019; 6: e459-e469Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar In the future, NEK2 inhibition could improve the therapeutic efficacy of proven PD-1/PD-L1 blockers. In addition to INH154, other NEK2 inhibitors with different modes of action are currently undergoing preclinical testing.10Dana D. Das T. Choi A. Bhuiyan A.I. Das T.K. Talele T.T. Pathak S.K. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development.Molecules. 2022; 27347Crossref Scopus (2) Google Scholar The efficacy and toxicity of these inhibitors in combination with, e.g., pembrolizumab (anti-PD-1) or durvalumab (anti-PD-L1) in patients with MM remain to be established in clinical studies. In conclusion, this study demonstrates that NEK2 inhibition disrupts the immune-tolerant bone marrow microenvironment, enhances the host's immune responses, and holds high promise for the development of novel therapeutic strategies to treat MM. The authors declare no competing interests.